MDMA was first made in 1912 as an accidental byproduct of a search for anticoagulants. Its potential would not be explored for another half century until the 1970s when the American chemist Alexander Shulgin experimented with the drug and noted its ability to generate feelings of emotional connection. He then introduced it to a group of therapists who used its effects on trust and empathy to bolster their therapeutic effectiveness. Soon however, it spread to the party scene and only a decade later, in 1985, the DEA made the drug illegal classifying it as Schedule 1, drugs with no known clinical use, which halted further research.
Over the last two decades, research into MDMA has reemerged alongside other Schedule 1 drugs such as LSD and psilocybin (magic mushrooms). These substances have been studied as new treatments for mental illness that may be able to counter some of the limitations of current medical treatment, including:
- Partial response: around a third of those with depression will not improve after two treatments.
- Long term need for medication: while some people can stop, many relapse after stopping medication. (Rifkin-Zybutz R. & Jauhar S., 2021)
- Side effects of current treatments: Many people dislike characteristic side effects of traditional antidepressants such as emotional numbness, sexual dysfunction or weight gain. (Ashton et al., 2005)
- Slow improvement: Current treatments often take at least 1-2 weeks to start to work with maximal effects at 4-6 weeks.
Previously MDMA has mainly been studied as a treatment for PTSD (Borissova A. & Brooks P., 2022), with trials of fast acting antidepressants mainly limited to ketamine and psychedelics (DMT, Psilocybin, LSD). This new study (Kvam et al, 2025) is the first in the modern era to examine MDMA-assisted therapy as a treatment specifically for people with a primary diagnosis of major depressive disorder, rather than as a secondary outcome in PTSD research.
MDMA: From mental health treatment to party drug and back again.
Methods
This trial included 12 participants who received MDMA in two dosing sessions, one month apart, alongside nine 90-minute psychotherapy sessions. Participants were all over 18 years old and had at least moderately severe depression for between 3 months and 2 years.
Participants received:
- Session 1: 80 mg MDMA, followed by an optional 40 mg supplemental dose after 90-120 minutes.
- Session 2: 120 mg MDMA, followed by an optional 60 mg supplemental dose after 90-120 minutes.
This was a proof-of-principle study that tested feasibility, not definitive effectiveness and was open-label so both participants and experimenters knew what medication was being given. There was no control group.
Results
This proof-of-principle trial aimed to show three things:
- That this approach is possible to do in future studies (feasibility).
- There is initial evidence of a treatment effect (proof-of-principle efficacy).
- Side effects can be managed and there are no serious adverse events (safety and tolerability).
Is MDMA-assisted therapy feasible?
All clinical trials have specific inclusion and exclusion criteria to select eligible participants. However, if too many people are excluded, recruitment becomes difficult and the sample may no longer reflect the target population.
In this trial, 86 people were screened on the telephone, 21 were bought in for in-person screening and 15 were enrolled. Around 20% of people were ultimately eligible, suggesting feasibility. As a contrast, a recent successful psilocybin trial only recruited 5% of people screened.
15 people were enrolled in the trial, of these 3 left the trial prior to dosing (20%). Reasons for dropout included symptom improvement, difficulty forming a therapeutic alliance, and lack of social support. This dropout rate may reflect early-stage refinement of recruitment procedures.
Of note 3/12 patients who were dosed (25%) required additional integration ‘booster’ sessions, emphasising the need for flexible protocols in future trials and suggesting 9 sessions may not be enough for a significant proportion of individuals.
Overall, the study provided evidence it would be possible to run a larger scale trial.
Is there evidence of an MDMA-assisted therapy treatment effect?
Depression was measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). At 2 months post-treatment, participants improved on average by 19.3 points (SD: 8.3), with 75% remission (MADRS ≤12). At 4 months, improvement remained (mean: 18.4; SD: 11.8) with 8/12 still in remission.
Overall, this is a large effect size that suggests further investigation of MDMA-assisted therapy may be worthwhile.
Did MDMA assisted therapy seem safe?
There were 46 adverse events reported, of which 15 were moderate and 31 were mild. The most common side effects were headache, increased suicidal ideation and jaw muscle tightness. No serious adverse events were reported (e.g., life threatening events, or events causing hospitalisation or persistent disability).
Any increase in the intensity of suicidal ideation from baseline was recorded as an adverse event. Five of the 12 participants had experienced some level of increase in suicidal ideation after dosing; 3 were mild and 2 moderate in severity. Of these 4 were recorded as adverse events. In most cases suicidality increases were transient, resolving by follow-up, although in one participant it persisted at a reduced severity. No cases of suicidal ideation involved any intent to act on the thoughts. At a group level, overall suicidality scores were lower at all points in the study than at baseline.
Overall, the treatment was generally well tolerated. However, the pattern of fluctuating suicidal ideation highlights the importance of careful monitoring in future trials, alongside clear procedures for managing changes in risk during MDMA-assisted therapy.
This small open-label study showed that MDMA-assisted therapy was feasible, with some evidence of early reductions in depression and no serious adverse events, but some transient increases in suicidal ideation.
Conclusions
The authors concluded that:
The study met the primary objectives of safety and feasibility and provided indications of efficacy for MDMA-AT for MDD. Further studies with a randomised design are required to confirm these findings.
This study also showed that increasing intensity of suicidal thoughts is a common adverse event in MDMA-assisted therapy in depression which requires more exploration in future studies.
Who could have guessed? The way forward is more trials.
Strengths and limitations
This is an exciting new study that provides initial evidence that MDMA might be safe and effective in depression. However, as an early-stage study there are several limitations to be aware of.
Although the effects seem very impressive in size; small scale, open label studies of drugs with powerful subjective effects such as MDMA often have very large effects, which then reduce as trials get larger and more rigorous. For example, psilocybin (magic mushrooms) had very large effects in initial open label studies, which then reduced in size in later large-scale trials (Carhart-Harris et al., 2018; Mertens et al., 2026, COMPASS Phase 3 Results, 2025). Nevertheless, sustained remission in such a large percentage of individuals 4 months after dosing is promising. Therefore, these results are a great start but need to be taken as evidence of the need for more research rather than definitive proof that MDMA works.
The lack of a control group also makes it difficult to interpret the frequent increase in intensity of suicidal thoughts. Symptoms naturally fluctuate in depression and from this study alone it is hard to know if increases in suicidality are above this normal level. For example, in the placebo arm of a trial testing MDMA for PTSD 41.2% of individuals had a similar increase in the intensity of their suicidal ideation during the study, suggesting that this may just reflect fluctuations in suicidality that occur in mental illness (Mitchell et al., 2023).
Another limitation is the patient group recruited. As a commentary on the article notes, patients recruited had an average of 200 (!) hours of psychotherapy in their past, which is not an average person with depression. For example, a study in Canada found that only 13% of patients diagnosed with depression received more than 4 hours of therapy in the year of diagnosis (Puyat et al., 2016). This may mean that this is a group that is more primed than average to respond to MDMA and therefore might limit generalisability to the general population. However, as the authors point out, this also means that this is a group that is depressed despite all this input and may highlight how MDMA can enable breakthroughs for patients who are not getting better with existing treatments. This would in fact reflect how MDMA was first used in the 1970s. Nonetheless future trials will need to see if this protocol works as well with people with less experience of psychotherapy.
This study showed promising early effects and feasible delivery of MDMA-assisted therapy, but the open-label design, lack of control group, and highly pre-treated sample mean the findings need cautious interpretation.
Implications for practice
This early trial lays the foundation for further research assessing whether there is a role for MDMA for treating depression. Further research is required and there are several questions future studies will have to answer before this work can be considered in clinic:
1. Does efficacy remain as trials are scaled up and include a control arm?
This question will be more complicated in trials of MDMA as they are extremely difficult to blind due to their characteristic side effects (Zecharia A., 2025). This makes it impossible for the double-blind design to reduce bias in the way it normally does in clinical trials, as there is no blind! This is a fact that the entire psychedelic field is currently grappling with. Future trials will need to incorporate existing strategies to reduce this issue, such as using third party blinded assessors and active placebos or pragmatic trials that compare MDMA to existing treatments.
2. Is the increase in suicidality clinically significant or different to placebo?
While there were no serious adverse events reported in this trial, 42% of individuals had an increase in intensity of their suicidal ideation. Future trials will need to carefully monitor suicidality to compare this to fluctuations in suicidality in patients receiving a placebo.
3. Who does this treatment work for?
A unique aspect of psychedelics is their combination of the psychotherapeutic and psychopharmacological aspects of treatment. This study occurred in a group extremely well versed in long-term psychological therapy. Future work will need to establish if the same effects can be seen in a population with less experience working psychologically. Additionally, this trial excluded people who have been depressed for longer than 2 years. Patients with difficult-to-treat depression are likely to be the target group of novel, expensive therapies such as these. Future studies should also look to explore how MDMA is able to help those with longer term depression symptoms.
4. How could this treatment be implemented in a health setting?
The described treatment is extremely resource intensive. Participants had 13.5 hours of psychotherapy alongside 2 full day dosing sessions for a total of around 30 hours of contact time. Implementing this protocol in a health setting would be extremely expensive and likely reserved for patients who are more unwell or private practice where people can pay for treatment. This innately carries with it concerns about equity of provision if these treatments are eventually licenced.
Careful thought will be needed to assess how necessary certain aspects of treatments are (e.g. do patients need two dosings or just one). In addition to this, consideration of how treatments will be integrated into existing overstretched health systems such as the NHS are key for understanding how they will work in practice and ensuring that everyone can stand to benefit from them.
Overall, this study represents an important first step on the path to investigating MDMA as a treatment for depression. New treatments that work rapidly, that are different to existing therapies, and work for those where existing treatments do not, are important. However, further trials and careful investigation of any increases in suicidality is needed to assess if MDMA assisted therapy is a viable treatment for depression.
Early MDMA trial shows promise for depression, but unanswered questions on efficacy, safety, scalability and real-world delivery mean it remains far from clinical practice.
Statement of interests
Raphael Rifkin-Zybutz is a PhD student and psychiatrist who has worked in the psychedelic field for 4 years, is running a study involving psilocybin and has worked on several psychedelic clinical trials. He is currently funded by the Medical Research Council (MRC).
Editor
Edited by Éimear Foley. AI tools assisted with language refinement and formatting during the editorial phase.
Links
Primary paper
Tor-Morten Kvam, Ivar W. Goksøyr, Justyna Rog, Inger-Tove Jentoft van de Vooren, Lowan Han Stewart, Ingrid Autran, Mark Berthold-Losleben, Lynn Mørch-Johnsen, René Holst, Ingmar Clausen and Ole A. Andreassen (2025). MDMA-assisted therapy as a treatment for major depressive disorder: proof of principle study. British Journal of Psychiatry. https://doi.org/10.1192/bjp.2025.10320
Other References
Rifkin-Zybutz R and Jauhar S. Maintenance or discontinuation of antidepressants for depression? Findings from the ANTLER trial, The Mental Elf, 17 Nov 2021.
Borissova A and Brooks P. How could MDMA-assisted and psilocybin-assisted psychotherapy help people with depression and PTSD? The Mental Elf, 4 Nov 2022.
Zecharia A. Psychedelics and mental health: Can the field deliver on its promise? The Mental Elf, 9 Jul 2025.
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